The therapeutic effects of ursodeoxycholic acid as an anti-apoptotic agent

The dihydroxy bile acid, ursodeoxycholic acid (UDCA), has been in widesprea d clinical use in the Western world since the mid 1980s, when it was initia lly used for gallstone dissolution ([1,2]) and subsequently for the treatme nt of chronic cholestatic liver diseases ([3,4]). Many clinical trials of U DCA in a variety of cholestatic disorders established biochemical and clini cal improvements, and most importantly showed a significant prolongation of transplant-free survival after four years of treatment with UDCA in patien ts with primary biliary cirrhosis ([5]). Despite its clinical efficacy, the precise mechanism(s) by which UDCA improves liver function during cholesta sis is still a matter of debate ([6]). It was initially considered that the choleretic effect of UDCA, coupled with its ability to cause a marked shif t in the composition of the bile acid pool towards hydrophilicity, accounte d for its mechanism of action. In recent years, however, it has become evid ent that UDCA and its conjugated derivatives are capable of exerting direct effects at the cellular, subcellular, and molecular levels by stabilising cell membranes, affecting signal transduction pathways, and regulating immu ne responses. In addition, we have shown that UDCA plays a unique role in m odulating the apoptotic threshold in both hepatic and non-hepatic cells ([7 -10]). The purpose of this article is to examine the mechanism(s) by which UDCA prevents apoptotic cell death associated with cholestasis. In addition , we will also review a potentially novel and, heretofore, unrecognised rol e of UDCA as a therapeutic agent in the treatment of non-liver diseases ass ociated with increased levels of apoptosis as a pathogenesis of the disorde r.